Systemic lupus erythematosus (SLE), an autoimmune disease primarily affecting young females, is characterized by hyperproliferation of T-lymphocytes; development of autoantibodies directed against nuclear antigens, particularly double-stranded DNA; and immune complex mediated pathology [R. Bartlett, Scand. J. Rheum., 75:290 (1988 Supp.)]. Complexation of the nuclear autoantibodies with their respective antigens, which are subsequently deposited in the small blood vessels, is a direct cause of many of the clinical manifestations of SLE.
Clinical manifestations of SLE are observed in almost all organ systems [see, I. McKay, Autoimmune Diseases, Charles C.. Thomas, pub., p.70]. These typically include a facial erythematous rash with a "butterfly" distribution over the nose and cheeks. Arthritis and arthralgia most commonly affecting the phalangeal and carpal joints are observed in a majority of SLE patients. Renal involvement is observed in approximately 70% of SLE patients, and is considered to be one of the major causes of mortality from SLE. Glomerulonephritis secondary to the deposition of autoantibody-antigen complex in the kidney, often leads to renal impairment, as observed by proteinuria, or ultimately renal failure. Clinical manifestations of SLE also are observed in the lymphatic, pulmonary, gastrointestinal, hemic, vascular, and central nervous systems.
Current treatment of SLE depends on the location and severity of the disease; with the method of treatment often dictated by the organ system affected. Arthritis or arthralgias can often be controlled with aspirin or other non-steroidal anti-inflammatory drugs. More severe manifestations of SLE such as hemolytic anemia, thrombocytopenic purpura, and severe polyserositis have been treated with prednisone. Currently recommended treatment for renal impairment utilizes combinations of prednisone with immunosuppressive agents such as azathioprine or cyclophosphamide.
As none of the methods of treatment presently available are completely satisfactory, current research has focused on developing agents for the treatment of SLE. Several animal models have been utilized to study the etiology of SLE and to evaluate potential forms of treatment.
The MRL/MpJ/lpr/lpr (MRL/lpr) mouse is a standard animal model for SLE, in which the autosomal recessive allele, lpr (lymphoproliferation) is associated with severe lymphadenopathy, early auto-antibodies, circulating immune complexes, glomerulonephritis, splenomegaly, arthritic changes, pulmonary lesions [Y. Kono, Int. J. Immunother. (2), 149 (1986)], progressive histopathological changes including lymphocytic and monocytic cell infiltrations, and inflammation and destruction of normal tissue architecture; all which contribute to early death (6 months). These manifestations, which are at least partially caused by hyperproliferation of dysfunctional T-lymphocytes, begin to appear at approximately 8 weeks of age. The MRL/MpJ +/+ is without the recessive gene, lpr, and therefore has a normal lifespan (2 yrs) with only mild and late symptoms of arthritis and glomerulonephritis. The MRL/lpr mouse is characterized by lymphadenopathy of double negative (L3T4.sup.-, Lyt-2.sup.-) lymphocytes [Kotzin, J. Exp. Med. 168:2221 (1988)] which have lost the normal T cell functions of concanavalin A (Con A) responsiveness and interleukin-2 production (R. Cameron, Immunol 59: 187 (1986)]. Therefore, a growing suppression of mitogenic responsiveness and IL-2 production is seen with disease progression.
The immunosuppressants cyclosporine A (CsA) and FK-506, have been evaluated in the MRL/lpr model of SLE. A decrease in lymphadenopathy was observed in MRL/lpr mice treated with 25 mg/kg of CsA. However, at this dose there was no improvement in glomerulonephritis (as evidence by a decrease in kidney function and albuminuria), no change in anti-DNA or anti-IgG autoantibody levels, and no prolongation of lifespan [J. Berden, Scand J. Immunol. 24:405 (1986)]. At a dose of 40 mg/kg, CsA decreased lymphadenopathy, arthritis, and glomerulonephritis and increased the survival time of the MRL/lpr mice, but did not affect levels of anti-DNA autoantibodies [J. Mountz, J. Immunol. 138: 157 (1987)].
A decrease in proteinuria and the progression of neuropathy, and an increase in survival time was observed in MRL/lpr mice that were treated with 2.5 mg/kg of FK-506; however, no change in levels of anti-DNA autoantibodies were observed [K. Takabayshi, Clin. Immunol. Immunopath. 51:110 (1989)].
Rapamycin, a macrocyclic triene antibiotic produced by Streptomyces hygroscopicus [U.S. Pat. No. 3,929,992] has been shown to prevent the formation of humoral (IgE-like) antibodies in response to an albumin allergic challenge [Martel, R., Can. J. Physiol.. Pharm. 55:48 (1977)], inhibit murine T-cell activation [Strauch, M., FASEB 3:3411 (1989)], and prolong survival time of organ grafts in histoincompatible rodents [Morris, R., Med. Sci. Res. 17:877 (1989)].